Transdermal delivery is desirable to reduce the side effects associated with the oral administration of drugs. Such side effects can include abdominal pain, nausea and vomiting. Further, transdermal delivery offers a patient freedom from injections and surgical implantations. Transdermal delivery also bypasses the significant metabolism associated with oral administration of drugs. Transdermal delivery is generally provided through a transdermal patch which provides sustained release of a drug.
Following its application to the skin, the therapeutic efficacy of a drug for transdermal delivery mainly depends on its ability to penetrate the skin fast enough to provide the plasma concentrations required to elicit the desired pharmacological activity. A large majority of drugs are unable to cross the skin at therapeutic rates due to the barrier imposed by the skin's outer stratum corneum layer. Thus, the main challenge in transdermal drug delivery is providing sufficient drug penetration across the skin. Skin permeability can be increased through the use of chemical enhancers, electrical enhancers via electroporation or iontophoresis, ultrasonic enhancers, and a variety of other approaches. Although these enhancement technologies are still under active investigation, delivering macromolecules into the skin remains a significant challenge. See, e.g., Park et al., J. Control. Release 104 (2005) 51-66 and Martanto et al., Pharm. Res. 21 (2004). One of the strategies used to enhance skin permeation of poorly permeable drugs is the codrug approach.
A codrug comprises two different drugs within a single chemical entity. The two drugs may be connected either directly or by means of a cleavable, biolabile covalent linker. Many diseases are treated by a combination of therapeutic agents that are co-administered in separate dosage forms. However; there are potential advantages in delivering the co-administered agents as a single chemical entity. One advantage is that often, when the two drugs are chemically linked together in the codrug structure, the resulting physicochemical and pharmacokinetic properties of the codrug are superior to those of the individual parent drugs. Thus, careful design of the codrug entity can afford a unique product that may have superior physicochemical properties for drug delivery, compared to those of the individual drug entities themselves, leading to improved pharmaceutical properties. In addition, there are also other factors, such as the ability to control drug delivery by appropriate design of the biolabile linker(s) connecting the two drug entities, and the effect that simultaneous delivery of the two drugs, as one chemical entity, will have on the pharmacokinetics of each respective drug. Because the skin and plasma have an abundance of esterase enzymes, codrugs with esterase-susceptible linkages can be cleaved by these enzymes to release the active parent drugs in tissue and plasma.
A codrug or a mutual prodrug consists of two drugs chemically linked together in order to improve the drug delivery properties of one or both drugs. This unique concept of a codrug has been utilized to improve ocular delivery of an antiglaucoma agent, ethacrynic acid (Cynkowska et al., Bioorganic & Medicinal Chemistry Letters 15 (2005) 3524-3527). Other examples of codrugs include facilitated gastrointestinal absorption of low molecular weight heparin (LMWH) via conjugation to deoxycholic acid (DOCA) to form LMWH-DOCA (Lee et al., J. Control. Release 111 (2006) 290-298) and dual-acting thromboxane antagonist-synthase inhibitors (Brown et al., Bioorganic & Medicinal Chemistry Letters 6 (1996) 273-278).
Opioid agonists are useful for treatment of a number of conditions, including chronic pain, acute pain and depression. Opioid antagonists are useful for treatment of alcohol dependence, opioid addiction, and smoking. Naltrexone (NTX), for example, is an opioid antagonist used in the treatment of opiate addiction and alcohol dependence (Volpicelli et al., Arch Gen Psychiatry 49 (1992) 876-80 and Wand et al., Alcohol Clin Exp Res 24 (2000) 1385-91). 6-β-naltrexol (NTXOL) is the active metabolite of NTX (Volpicelli, Lancet 346 (1995) 456 and Verebey et al., Clin Pharmacol Ther 20 (1976) 315-28). Naltrexone is currently available as REVIA®, an FDA approved 50 mg tablet of Naltrexone Hydrochloride, and as VIVITROL™, the recently FDA approved 28-day controlled release 380 mg depot form of Naltrexone. However, REVIA® is poorly bioavailable, with documented side effects (PDR, Medical Economics, 1996, 2229-2233, New Jersey). In addition, although long-lasting Naltrexone depot formulations have shown plasma levels for up to 30 days (Galloway et al., BMC Psychiatry 5 (2005) 18), once VIVITROL™ is injected, it cannot be easily discontinued without painful surgical removal. There is a need for methods for transdermally transporting a therapeutically effective amount of opioid antagonists and agonists, such as Naltrexone, in order to provide benefits such as controlled release, reduced side effects, and the ability to readily discontinue therapy.
Bupropion (BUP) is an aminoketone used as an antidepressant and non-nicotine aid to smoking cessation (Johnston et al., Nicotine Tob Res 3 (2001) 131-40). The pharmacological activity of BUP might be due to, or receive substantial contributions from its major active human metabolite, hydroxybupropion (BUPOH) (Schroeder, J Clin Psychiatry 44 (1983) 79-81 and Belson and Kelley, J Emerg Med 23 (2002) 223-30). Both BUP and BUPOH have excellent physicochemical properties that allow for transdermal delivery, and chemical linkage to BUP or BUPOH should improve the skin permeability characteristics of opioid antagonists and agonists.
The present invention is directed to novel codrugs comprising bupropion or hydroxybupropion and an opioid antagonist or an opioid agonist joined together by chemical bonding. The codrugs provide a significant increase in the transdermal flux across human skin, as compared to the basic opioid antagonist or opioid agonist. Preferably, the opioid antagonist is NTX or NTXOL. The codrug of the present invention may increase the transdermal drug delivery rate either by a solubility improvement or by a permeability improvement, or a combination of both.